tbuckley/cabot-search huggingface dataset:
Neuron stem cell NLRP6 sustains hippocampal neurogenesis to resist stress-induced depression
Authors: Chuanfeng Tang, Qiaona Wang, Jingyan Shen, Congying Wang, Hong Ding, Shiyu Wen, Fan Yang, Ruiqing Jiao, Xingxin Wu, Jianmei Li, Lingdong Kong
Journal: Acta Pharmaceutica Sinica B (2023)

Neurogenesis decline in hippocampal dentate gyrus (DG) participates in stress-induced depressive-like behaviors, but the underlying mechanism remains poorly understood. Here, we observed low-expression of NOD-like receptor family pyrin domain containing 6 (NLRP6) in hippocampus of stress-stimulated mice, being consistent with high corticosterone level. NLRP6 was found to be abundantly expressed in neural stem cells (NSCs) of DG. Both Nlrp6 knockout (Nlrp6-/-) and NSC-conditional Nlrp6 knockout (Nlrp6CKO) mice were susceptible to stress, being more likely to develop depressive-like behaviors. Interestingly, NLRP6 was required for NSC proliferation in sustaining hippocampal neurogenesis and reinforcing stress resilience during growing up. Nlrp6 deficiency promoted esophageal cancer-related gene 4 (ECRG4) expression and caused mitochondrial dysfunction. Corticosterone as a stress factor significantly down-regulated NLRP6 expression, damaged mitochondrial function and suppressed cell proliferation in NSCs, which were blocked by Nlrp6 overexpression. ECRG4 knockdown reversed corticosterone-induced NSC mitochondrial function and cell proliferation disorders. Pioglitazone, a well-known clinical drug, up-regulated NLRP6 expression to inhibit ECRG4 expression in its protection against corticosterone-induced NSC mitochondrial dysfunction and proliferation restriction. In conclusion, this study demonstrates that NLRP6 is essential to maintain mitochondrial homeostasis and proliferation in NSCs, and identifies NLRP6 as a promising therapeutic target for hippocampal neurogenesis decline linked to depression.
Association of intermittent vs continuous androgen deprivation therapy with cardiovascular disease and endocrine/metabolic disorders in patients with metastatic prostate cancer.
Authors: Alicia K. Morgans, Ramin Ebrahimi, Priyanka J. Bobbili, Esmond Nwokeji, Raj Gandhi, Raj Desai, Krisztina Horvath, Michael Ryan, Sarah Hanson, Mei Sheng Duh, Mark A. Preston
Journal: Journal of Clinical Oncology (2023)

82 Background: There is mixed evidence on the risks of cardiovascular disease (CVD) and endocrine/metabolic disorders associated with long-term intermittent and continuous androgen deprivation therapy (iADT and cADT, respectively) for metastatic prostate cancer (mPC). This study examined these risks in patients (pts) with mPC receiving iADT vs cADT in the US. Methods: This was a retrospective cohort study of SEER-Medicare pts with mPC initiating ADT (2010–2017), with ≥36 months of continuous insurance coverage, unless death occurred, who did not receive chemotherapy or a second-generation anti-androgen during follow-up. iADT and cADT cohorts were defined by treatment patterns and gaps in therapy. Comorbidities and clinical events were identified using ICD-9/10-CM codes. Outcomes examined were major adverse cardiovascular events (MACE [myocardial infarction (MI), stroke, cardiomyopathy/heart failure (HF), pulmonary embolism (PE), ischemic heart disease (IHD), or all-cause mortality]) and endocrine/metabolic events (diabetes, hypercholesterolemia, bone fractures, or osteoporosis). Inverse probability of treatment weighting (IPTW) was used to adjust for differences between cohorts; weighted Cox models were used to estimate the hazard ratio (HR) of the outcomes. Subgroup analyses examined pts by CVD history; a sensitivity analysis was performed restricting the definition of MACE to include CVD-related mortality as a component, i.e., MACE SA (MI, stroke, cardiomyopathy/HF, PE, IHD, or CVD-related mortality). Results: 2234 pts with mPC were included; 478 (21%) received iADT and 1756 (79%) cADT. Median follow-up time was 27 and 13 months, and time on ADT (excluding gaps for iADT pts) was 24 and 19 months for the iADT and cADT cohorts, respectively. Deaths occurred in 39% of iADT pts vs 55% of cADT pts; PC was the most common cause of death in both cohorts. In adjusted analyses, pts receiving cADT had a higher risk of MACE vs iADT. No differences in risk of endocrine/metabolic events were observed. Subgroup analysis showed that baseline history of CVD did not alter the results for MACE. Sensitivity analysis results showed no difference in risk of MACE SA between pts receiving cADT vs iADT. Conclusions: Pts with mPC receiving cADT had a higher risk of MACE (including all-cause mortality), and no difference in risk of endocrine/metabolic events, compared with those receiving iADT. When MACE was restricted to include CVD-related mortality, there was no difference in risk between cohorts. [Table: see text]
Longitudinal detection of circulating tumor DNA in patients with advanced renal cell carcinoma.
Authors: Arnab Basu, Revathi Kollipara, Sumedha Sudhaman, Tamara Mahmood, Natalia Pajak, Carcia Carson, Punashi Dutta, Mark Calhoun, Adam ElNaggar, Minetta C. Liu, James Ferguson, Charles Peyton, Soroush Rais-Bahrami, Alan Tan
Journal: Journal of Clinical Oncology (2023)

715 Background: Treatment response monitoring is key to effective disease management for patients with advanced (RCC) and can potentially improve clinical outcomes. Circulating tumor DNA (ctDNA) has shown promise as a biomarker in the early identification of treatment response in a variety of tumor types. Herein, we evaluated ctDNA-derived molecular residual disease (MRD) detection and dynamics in both clear cell (ccRCC) and non-clear cell (nccRCC) RCC patients treated with standard of care therapy and provide correlations with clinical outcomes. Methods: This was a multi-center retrospective analysis of real-world data obtained from commercial ctDNA testing (Signatera, Natera, Inc.), 41 patients (142 plasma samples) with high-risk resected or metastatic RCC were analyzed for ctDNA. Clinical data were collected on IMDC risk category, pathologic subtype, tumor stage and grade including the presence of sarcomatoid/rhabdoid features. Progression on radiological imaging was based on RECIST 1.1. criteria. Results: Of the 41 patients, 73% (30/41) had ccRCC and the remaining 27% (11/41) were nccRCC. Immunotherapy was administered as a single agent or in combination with other immune checkpoint inhibitor agents/targeted therapy in 78% (32/41) in either frontline or refractory settings. ctDNA detection at any time point was 70% (29/41) and patients were followed-up for a median of 26.4 weeks (range: 0.9-90.6) from the first ctDNA time point. Fourteen patients (34%) experienced disease progression during follow-up and all had ctDNA detected ahead of radiological progression (100% sensitivity) with a median lead time of 13.6 weeks (range: 1-39.7 weeks). Concordance between clinical outcome and ctDNA status (detected or not detected) was observed in 78% (32/41) of the patients, 12% (5/41) showed discordance, and imaging data is pending for 10% (4/41) at the time of analysis. Conclusions: Collectively, our study demonstrates high concordance between MRD status and subsequent clinical outcomes. MRD had 100% sensitivity for predicting subsequent radiographic progression with significant median lead time. MRD may serve as a valuable tool for monitoring patients on immunotherapy-based regimens for RCC.
2022 Global patient survey: Reported experience of diagnosis, management, and burden of renal cell carcinomas.
Authors: Rachel H. Giles, Deborah Maskens, Lorenzo Marconi, Robin Martinez, Karin Kastrati, Carlos Castro, Juan Carlos Julian Mauro, Robert Bick, Margie Hickey, Daniel Yick Chin Heng, James Larkin, Axel Bex, Eric Jonasch, Sara Jane Maclennan, Michael A.S. Jewett
Journal: Journal of Clinical Oncology (2023)

653 Background: Kidney cancer (renal cell carcinoma, RCC) has shown a sustained increase in its global prevalence thereby presenting increasing burden to health systems, and most of all, to individual patients and their families. Little is known about the variations in the patient experience and best practices among countries. Although individual national surveys have been held, no conclusions could be drawn about country-level variation in patient experience or best practice. Here, we report on the 3rd biennial Global Patient Survey on the diagnosis, management, and burden of Renal Cell Carcinomas conducted by the International Kidney Coalition (IKCC) and involving its Affiliate Organisations worldwide in 15 languages. The aim of the survey was to improve collective understanding and to contribute toward the reduction of the burden of kidney cancer around the world. Methods: A 35-question survey on the diagnosis, management, and burden of RCC was designed by a multi-country steering committee of patient leaders to identify geographic variations in 6 key dimensions: patient education, experience and awareness, access to care and clinical trials, best practices, quality of life, and unmet psychosocial needs. EAU, ESMO, ASCO and NCCN Guidelines committees provided topics of interest to support evidence-based medicine (eg patient perspective on active surveillance, biopsies, etc) . The survey was distributed to patients with kidney cancer and their caregivers in 15 languages, through social media and IKCC’s 49 Affiliate Organizations and/or allied organizations who are not formal affiliates. It was completed online or in paper form between 26 September 2022 and 31 October 2022. At the time of this abstract submission, the survey was still open for completion. Results: We will present the top-line results of the 2022 survey for the very first time. Survey results will be analyzed using cross-tabulations by an independent third-party organization, and multi-variate analysis of predetermined variable will be performed. The full global report will be presented, as well as individual country reports where at least 100 responses were received. Conclusions: The IKCC and its global affiliates will be using the results to ensure that patients’ voices are heard. Actionable points will suggest future projects. Furthermore, individual countries can use their reports to advance their understanding of patient experiences and to drive improvements in care provision locally.
Dissecting the molecular signatures underlying hybrid oncocytic tumors in Birt-Hogg-Dubé syndrome.
Authors: Xiaoming Wang, Rahul Mannan, Yupin Zhang, Margaret Hogan, Dana King, Anya Chinnaiyan, Arul Chinnaiyan, Saravana Dhanasekaran, Rohit Mehra
Journal: Journal of Clinical Oncology (2023)

707 Background: Birt-Hogg-Dubé (BHD) syndrome is associated with an increased risk of renal tumors including the hybrid oncocytic tumors (HOT), renal oncocytoma (RO) and chromophobe renal cell carcinoma (CHRCC). HOT are known to exhibit morphological features overlapping between RO and CHRCC. The molecular underpinnings of HOT and the corresponding morphologic correlates remain poorly understood. Herein we aimed to understand the distinct molecular features underlying HOT and how the genomic phenotype differs from CHRCC. Methods: We performed next generation sequencing and single cell sequencing analysis to understand the clinico-pathologic aspects and tumor biology of HOT and CHRCC, including tumor development. This was followed by spatial transcriptome analysis of the distinct HOT tumor compartments, using nanoString GeoMX digital spatial profiler. The candidate biomarker expression was confirmed by immunohistochemistry (IHC) and RNA in situ hybridization (RNA-ISH), a unique gene expression visualization molecular technology. Results: We discovered unique gene expression signatures underlying the two distinct morphological patterns seen in HOT. FOXI1 and L1CAM show a striking mutually exclusive expression pattern in the two cellular populations seen within this tumor. The signature genes of RO like cells seen within HOT resembles the principal cells of the distal nephron seen in normal kidney; and the signature genes of the CHRCC like cells resembles the intercalated cells of the distal nephron. This suggests distal nephron as the cellular site of origin for HOT. We also nominated tumor specific biomarkers for HOT. Conclusions: We identified unique gene expression signatures which are definitional for HOT and nominated candidate diagnostic biomarkers to help distinguish HOT from other renal tumor subtypes with overlapping morphology. This finding would improve the diagnostic accuracy, assist familial genetic monitoring, and facilitate disease management.
Leukocyte subtypes and myeloid derived suppressor cells as prognostic markers in metastatic castration resistant prostate cancer treated with cabazitaxel: A satellite study of the CABASTY phase III trial.
Authors: Jean-David Heisbourg, Stephane Oudard, Philippe Beuzeboc, Mostefa Bennamoun, Carolina Saldana, Eric Voog, Philippe Barthelemy, Antoine Thiery-Vuillemin, Ali Hasbini, Nadine Houede, Houda Belhouari, Carole Helissey, Beatrice Parfait, Marion Thibaudin, Letuan Phan, Salma Kotti, Eric Yaovi
Journal: Journal of Clinical Oncology (2023)

126 Background: CABASTY trial investigated the benefit of an adapted schedule of cabazitaxel (16 mg/m 2 bi-weekly versus 25 mg/m 2 tri-weekly) in mCRPC patients previously treated with docetaxel and alternative androgen-targeted therapy. The study met its endpoints with a significantly decreased incidence of grade ≥ 3 neutropenia without a decrease in overall survival. This preplanned analysis evaluated the prognostic impact of neutrophil-to-lymphocyte ratio (NLR), neutrophil-to-platelets ratio (NPR) myeloid derived suppressor cells (MDSC) and leukocyte subtypes counts in this setting. Methods: 44 patients treated with cabazitaxel were included. Peripheral blood mononuclear cells were isolated and myeloid compartment analysis were performed at baseline, week 6 (S6) and week 12 (S12) of treatment using a multi-parametric flow cytometry panel. We investigated at each timepoints the association of NPR, NLR, MDSC and leukocytes subtypes with PSA response rate (PSArr), Progression Free Survival, and Overall Survival with a preplanned uni- and multivariate analysis. Results: The NLR, NPR, MDSC subtypes and lymphocytes count at baseline were prognostic in the CABASTY trial regardless of the cabazitaxel regimen. Patients with a high lymphocyte count and/or a low NLR, NPR, and MDSC counts at baseline had a significantly improved PSAr, PFS and OS. In the multivariate analysis, a NPR &gt; 1,84 and lymphocytes count &lt; 1,2 G/L at baseline were significantly associated with OS [HR 2.007 (1.3 - 3.1)] and [HR 0.38 (0.20 - 0.73)]. Conclusions: High NLR, NPR, neutrophil and MDSC counts as well as a low lymphocyte count at baseline and during treatment predict poor outcomes in mCRPC patients treated with cabazitaxel. NPR and lymphocyte count are readily available biomarkers that may be useful for risk stratification in future clinical trials and could be incorporated into prognostic nomograms. Clinical trial information: NCT02961257 .
Real world analysis of peritoneal metastasis from renal cell carcinoma: Meet-Uro 27 study.
Authors: Marco Stellato, Sebastiano Buti, Marco Maruzzo, Giuseppe Fotia, Mariella Sorarù, Maria Bassanelli, Brigida Anna Maiorano, Francesco Grillone, Luca Galli, Roberto Filippi, Martina Fanelli, Michele Dionese, Michele Maffezzoli, Bruno Vincenzi, Giuseppe Procopio, Elena Verzoni
Journal: Journal of Clinical Oncology (2023)

638 Background: Peritoneal metastases (PM) have been reported in approximately 1% of patients (pts) with metastatic Renal Cell Carcinoma (mRCC). Outcome data are limited due to the rarity of this metastatic site. Therefore, the aim of our study is to describe RCC pts with PM treated as per clinical practice. Methods: Baseline characteristics and outcome data of pts with PM from RCC were retrospectively collected from 12 Italian oncological referral centers adhering to the Meet-Uro group, from January 2016 to September 2022. Results: We collect 91 RCC pts with PM. 87/91 pts received systemic treatment, 4/87 only best supportive care. First line treatment included TKI and ImmuneOncology(IO)-TKI with different Objective Response Rate(ORR) (41% vs 53.8%, respectively) and Disease Control Rate (DCR) (57.1% and 80.7%, respectively) as well as median PFS (9.9 mo (95%CI 4.5-15.4) for TKI and not reached (NR) for IO-TKI (69.7% pts were free from progression at a median follow up of 13.8 months). Primary refractory (PR) pts were 35.7% for TKI and 7.7% for IO-TKI. According to IMDC score, mPFS was consistent among risk categories, 36.8 mo (95%CI 9.6-63.9) for good risk pts, 13.8 mo (95%CI 8.8-18.8) for intermediate pts and 2.9 mo (95%CI 2.2-3.7) for poor risk pts. Synchronous PM was associated to shorter mPFS 11.0 (95%CI 3.1-19.0) compared to patients with metacronous involvement as well as ORR (31.3%) and DCR (43.1%) whereas PR was higher (34.7%). Only 43/87 pts (45.7%) received a second line treatment that was TKI ( ORR 30.7%; DCR 61.5%; or IO (ORR 20.6%; DCR 41.3%). mOS was 21.8 mo (12.0-31.5) for TKI and NR for pts treated with IO-TKI (80.8 alive at 1 yrs). According to IMDC score, mOS was NR for good risk pts, 24.6 (95%CI 15.8-33.3) and 3.4 (95%CI 2.4-4.3) for intermediate and poor risk, respectively. Conclusions: We report one of the largest case series regarding PM from RCC. Poor risk patients according to IMDC score, sarcomatoid feature and liver metastasis were more represented in our population, compared to historical control, suggesting a more aggressive behavior of PM mRCC. Outcome data suggest that TKI-IO as first line treatment, compared to TKI monotherapy, and TKI as second line, compared to IO, are more active treatment for these pts with dismal prognosis. Nevertheless, synchronous PM has been reported in 57% of pts with poorer outcome and lower response rate. [Table: see text]
Financial toxicity in patients with metastatic renal cell carcinoma on combination therapy.
Authors: Michael D. Staehler, Hedyeh Ebrahimi, Ulka N. Vaishampayan, Severin Rodler, Sumanta Monty Pal, Dena Battle
Journal: Journal of Clinical Oncology (2023)

651 Background: Combination therapy based on immunotherapy (IO) alone or in combination with oral tyrosine kinase inhibitors (TKI) has become the standard of frontline therapy in metastatic renal cell carcinoma (RCC). We sought to ascertain real world data on financial implications in RCC patients on combination therapy. Methods: An online survey was administered by Kidney Cancer Research Alliance (KCCure), a non-profit patient advocacy group, between 07/2022 and 09/2022 to patients via website, mailing lists and social media platforms. Multiple responses from the same patient were prohibited via anonymized IP address tracking. Select questions were directed at questions related to financial concerns as well as the validated 11-item COST measure and out-of-pocket spending patterns related to supplement purchases. Pearson’s correlation (r) and Kendal’s tau test were used to analyze the COST questionnaire, financial burden and hardship. Significance levels were 2 tailed. Results: 289 responders were on combination therapy (IO+IO or IO+TKI) (M:F, 145:143). Median age was 61 (range 19-89). 177 pts answered the COST questionnaire. Patients identified themselves as white (91%), living in the US (86.8%) and had a bachelor's degree or beyond (52.9%). 21.1%, 46.1%, and 32.6% lived in urban, suburban, and rural locations. The approximate annual household income was &lt;50.000US$ in 17%, &lt;100,000US$ in 41% and &gt;200,000US$ in 15%. 61% had private insurance, 27% were on Medicare/Medicaid and 0.6% were uninsured. 14% reported that it was difficult or very difficult to pay their premiums. 31% were retired and 24% not able to work. 28% reported that their medical situation has not reduced their income at all and 26% claimed that their disease reduced their income very much. Significant financial, medical, behavioral, psychological and emotional hardship was reported by 15%, 26%, 12%, 19% and 24% of the patients respectively. The monthly out of pocket costs were independent of type of therapy with 50% of the patients reporting spendings of &lt;50US$. 36% reported high out of pocket costs are a barrier to care. 44% have received financial support through a manufacturer or a foundation.22.4% of responders reported spending &gt;$100/month on supplements, and 8.3% reported spending &gt;$250/mo. Median COST score was 22 (range 4-36). COST score was significantly correlated to age, NCCN distress score, time since diagnosis and supplement intake (p&lt;0.05). Conclusions: Systemic therapy imposes financial hardship on patients but does not seem to be worse with combination therapy in RCC. Route of administration is not influencing financial hardship. Patients are willing to pay for out supplements if their treatment is not causing financial harm.
Inherited mutations in DNA damage gene repair (gDDR) in Italian men with metastatic prostate cancer.
Authors: Ugo De Giorgi, Chiara Casadei, Vincenza Conteduca, Giorgia Gurioli, Emanuela Scarpi, Maria Concetta Cursano, Nicole Brighi, Cristian Lolli, Giuseppe Schepisi, Umberto Basso, Giuseppe Fornarini, Sara Bleve, Alberto Farolfi, Amelia Altavilla, David Olmos, Elena Castro
Journal: Journal of Clinical Oncology (2023)

223 Background: The need for genetic prognostic and predictive markers is urgent in order to identify potential target therapies or personalized therapeutic sequences for men with metastatic prostate cancer (mPC). The prevalence of pathogenic germline mutations in DNA damage repair (gDDR) such as germline mutations in BRCA2 (gBRCA) is well established: in the Anglo-American population with mPC was 5.3%, while in the Chinese population was 4.3% and in Spanish population 3.3%. This prospective multicenter cohort study evaluated the prevalence of gDDR alterations in the Italian population affected by mPC. Methods: In an observational prospective trial, 300 consecutive Italian patients affected by mPC were recruited between 2015 and 2019 and were screened for gDDR mutations in 107 genes. The primary aim was to assess the frequency of ATM/BRCA1/BRCA2/PALB2 germline mutations in the Italian population of patients with mPC. Secondary aims included the association of gDDR subgroups with metastatic onset, Gleason Score ≥8, and time to castration resistance. Results: We analyzed 300 patients and we identified 297 valuable patients. 46 patients had a pathogenic/likely pathogenic variants (15.4%): the more frequent is gBRCA2 in ten cases, gATM in five (1.7%), gMUTYH in four cases (1.3%), gCHEK2 in three cases (1%) and one case in PALB2 (0.3%). No mutations in BRCA1 were identified. We also highlighted six patients (2%) with clonal hematopoiesis of indeterminate potential (CHIP) interference in ATR (n=2), ATM (n=2), CHEK1 (n=1) and BRIP1 (n=1). Finally, we identified 117 alterations of variants of unknown significance (VUS) in 98 patients. In a univariate analysis, the median time to castration resistance in gBRCA2 patients was 11.6 months versus 22.3 months in patients with other mutation versus 23.4 months in no mutated patients. There were no associations of gDDR subgroups with metastatic onset and Gleason Score ≥8. Conclusions: The prevalence of gBRCA2 in the Italian population is 3%, which is similar to those of Spanish population, identifying interesting similarities between people of the Western Mediterranean area. The presence of gBRCA2 mutations correlates with lower time to the onset of castration resistant disease, according to a more aggressive phenotype.